Pharmacological Basis for Management of Drug Dependence

Abstract

Neurochemical mechanisms underlying development of drug dependence and withdrawal syndrome remain unclear. Several clinical features of withdrawal syndrome, such as anxiety, are considered to be common among patients with drug dependence induced by different drugs of abuse. In the present study, we investigated whether diazepam-binding inhibitor (DBI), an endogenous anxiogenic neuropeptide, participates in the anxiety associated with drug dependence and its withdrawal symptoms. When we examined brain from mice dependent on alcohol, nicotine, and morphine, we observed that the levels of DBI protein and its mRNA significantly increased. Abrupt cessation of these drugs facilitated further increases in DBI expression. In the cases of nicotine- and morphine-dependent mice, concomitant administration of specific antagonists for nicotinic acetylcholine and m-opioid receptors, respectively, abolished the increased expression. Similar patterns of DBI expression were observed in the neurons after sustained exposure to these drugs and its removal from culture medium. Sustained exposure of the neurons to abused drugs significantly increased the KCl (30 mM)-induced 45Ca2+ influx and enhanced expression of alpha1 subunits for L-type high voltage-gated Ca2+ channels (HVCCs). In addition, the increase in DBI expression was completely blocked by L-type HVCC inhibitors. Therefore, these alterations in DBI expression, mediated via increased influx of Ca2+ through upregulated L-type HVCCs, are closely related to drug dependence and/or its withdrawal syndrome and are considered to be part of a common biochemical process in drug dependence induced by different drugs of abuse.

Cardiovascular effect of nifedipine in morphine dependent rats: hemodynamic, histopathological, and biochemical evidence

“…The other possibility is the interaction of morphine and nifedipine on heart L-type Ca 2+ channels. In the central nervous system, chronic use of morphine enhances the L-type Ca 2+ channels' expression, augments the calcium entry in to cell, and increases basal free intracellular Ca 2+ concentration (5-7). Other effects of morphine are prolongation of action potential by augmentation of L-type calcium current (28) and increase in heart myofilament sensitivity to calcium (29).…”

“…Morphine is also effective in relieving chest pain (3), pulmonary edema, and heart failure after myocardial infarction (4). Morphine dependency is associated with an increase of L-type Ca 2+ channels' expression, increased calcium entrance to cells, and enhanced basal-free intracellular Ca 2+ concentration in the central nervous system (5-7). …”